Oxidative stress has been proposed as a pathogenic mechanism in Alzheimer's disease (AD) (P. F. Good et al., Am. J. Pathol. (1996) 149:21). Oxidative stress may also contribute to neuronal degeneration and death in disorders ranging from ischemic stroke to Alzheimer's and Parkinson's to age related macular degeneration to amyotrophic lateral sclerosis (M. P. Mattson et al., J. Neurosci. Res. (1997) 49:681), disorders in which nitric oxide, via peroxynitrite, plays a key role.
Several strategies for conferring neuroprotection have been developed which target the complex neurochemical processes which follow neuronal malfunction. Older approaches (reviewed by N. G. Wahlgren, in R. Green, “International Review of Neurobiology: Neuroprotective Agents and Cerebral Ischemia”, Vol. 40, Academic Press, 1997) including closure of calcium channels (with calcium antagonists), inhibition of glutamate release, and antagonism to NMDA and GABA agonism have not led to any remarkable treatments. With the recent emphasis on the role of reactive oxygen species (ROS) and of the nitrogen oxyanion species, the focus of possible treatments has now shifted to antioxidant and free radical scavengers (K. Hensley et al., in “Neuroinflammation: mechanisms and management” (Ed: P. L. Wood), Humana Press Inc., 1997). R(+)-6-(N-methyl,N-ethyl-carbamoyloxy)-N′-propargyl-1-aminoindan, also known as (3R)-3-(prop-2-ynylamino)-2,3,dihydro-1H-inden-5-yl ethylmethylcarbamate, is disclosed in PCT Application Publication No. WO98/27055 (U.S. Pat. No. 6,303,650, issued Oct. 16, 2001 to Chorev), the entire contents of which are incorporated by reference. This compound has been given the nonproprietary name ladostigil.
Ladostigil has been shown to inhibit acetylcholinesterase (ChE) and monoamine oxidase selectively in the brain (M. Weinstock et al., TV3326, a novel neuroprotective drug with cholinesterase and monoamine oxidase inhibitory activities for the treatment of Alzheimer's disease, J. Neural Transm. Suppl. (2000) 60:157-69). As such, ladostigil has been proposed for treatment of depression, Attention Deficit Disorder (ADD), Attention Deficit and Hyperactivity Disorder (ADHD), Tourette's Syndrome, Alzheimer's Disease and other dementias, neurotraumatic disorders and memory disorders in humans (see, e.g., U.S. Pat. No. 6,538,025, issued Mar. 25, 2003 to Chorev et al.). The following dosing of ladostigil has been disclosed: chronic administration of 52 mg/kg to treat comorbidity of dementia with Parkinsonism in a rat model (Y. Sagi, The neurochemical and behavioural effects of the novel cholinesterase-monoamine oxidase inhibitor, ladostigil, in response to L-dopa and L-tryptophan, in rats, Br. J. Pharmacol. (2005) 146(4):553-60); chronic administration of 17 mg/kg to treat hyperanxiety and depressive-like behaviour in a rat model (T. Poltyrev et al., Effect of chronic treatment with ladostigil (TV-3326) on anxiogenic and depressive-like behaviour and on activity of the hypothalamic-pituitary-adrenal axis in male and female prenatally stressed rats, Psychopharmacology (2005) 181(1):118-25); and chronic administration of 26 mg/kg to show brain selective MAO inhibition (M. Weinstock, Limited potentiation of blood pressure response to oral tyramine by brain-selective monoamine oxidase A-B inhibitor, TV-3326 in conscious rabbits, Neuropharmacology (2002) 43(6):999-1005, and M. Weinstock, Effect of TV3326, a novel monoamine-oxidase cholinesterase inhibitor, in rat models of anxiety and depression, Psychopharmacology (2002) 160(3):318-24, respectively). Ladostigil has also been shown to suppress apoptosis induced by the peroxynitrite-generating agent N-morpholino sydnonimine (Sin-1) in cultured dopaminergic neuroblastoma SH-SY5Y cells (Maruyama et al., Anti-apoptotic action of anti-Alzheimer drug, TV3326 [(N-propargyl)-(3R)-aminoindant-5-yl]-ethyl methyl carbamate, a novel cholinesterase-monoamine oxidase inhibitor, Neuroscience Letters (2003) 341:233-236).
MAO inhibitors (MAOIs) are known to have many contraindications, and are associated with high incidences of hypertensive crises (Physician's Desk Reference, 59th Ed. (2005) pgs. 1583-4).
ChE inhibition is known to lower body temperature. (Gordon, 1994) By stimulating muscarinic receptors in the pre-optic area of the hypothalamus, heat loss is promoted through peripheral vasodilatation. It has been shown that the fall in body temperature is proportional to the degree of brain ChE inhibition.
Disclosed herein is that ladostigil can be used to reduce the neurodegenerative effects of oxidative nitrative stress at dosage levels that do not cause the noted side effects related to inhibition of monoamine oxidase (MAO) or cholinesterase (ChE).